The objectives of this project are 1) to evaluate the neuroendocrine responses to surgical stress and inflammation, 2) to determine the analgesic and anti-inflammatory effects of prototype and novel drugs which alter either the synthesis or the receptor activation of neuroendocrine mediators, and 3) to evaluate the clinical utility of these novel drugs in controlled trials. This year, we have extended our research on the regulation of the pituitary release of beta-endorphin under conditions of stress by evaluating the effects of nonsteroidal anti-inflammatory drugs. Subjects undergoing the removal of impacted third molars received either ibuprofen or placebo one hour prior to oral surgery conducted with local anesthesia only. Blood levels were collected prior to drug administration, one hour following drug, intraoperatively and postoperatively and analyzed for beta-endorphin levels by radioimmunoassay. Preoperative administration of ibuprofen did not result in any change from baseline levels of beta-endorphin. In contrast, levels of beta-endorphin were significantly elevated during the stress of oral surgery. Parallel studies in rats and pituitary cell cultures showed a similar elevation when ibuprofen administration was combined with administration of corticotropin releasing factor. These results support the hypothesis that protaglandins suppress the pituitary release of beta endorphin and that suppression of prostaglandin levels by administration of a NSAID results in increased beta-endorphin release. A current study is attempting to replicate and extend these findings to postoperative pain. Subjects who have undergone oral surgery remain at the clinic until the onset of moderate to severe pain and are then administered either S(+)-ibuprofen, racemic ibuprofen, or placebo. Blood samples are collected for four hours following drug administration for the measurement of the isomers of ibuprofen and beta- endorphin. The S(+) isomer of ibuprofen is the active form of the drug and has been demonstrated to result in more rapid onset and higher blood levels than administration of the racemic mixture which requires hepatic conversion of the R(-) isomer to the S(+) isomer. Data has been collected for 140 of the 175 projected subjects and will be analyzed to determine if a relationship exists between the blood levels of the S(+) isomer, plasma levels of beta-endorphin, and pain relief.